BRPI0816814B1 - Composto, composição farmacêutica e uso de um composto - Google Patents

Composto, composição farmacêutica e uso de um composto Download PDF

Info

Publication number: BRPI0816814B1
Authority: BR; Brazil
Prior art keywords: amino; mmol; oxo; acid; alkyl
Prior art date: 2007-09-12

Application number

BRPI0816814-8A

Other languages

English (en)

Portuguese (pt)

Inventor

Kazuhiro Yumoto

Kyoko Okada

Shigeki Seto

Masahiro Nomura

Oana Cociorva

Yasumichi Fukuda

Yasushi Kohno

Bei Li

Ayako Nakamura

Katrin Szardenings

Original Assignee

Kyorin Pharmaceutical Co. Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2007-09-12

Filing date

2008-09-12

Publication date

2021-08-31

2008-09-12 Application filed by Kyorin Pharmaceutical Co. Ltd filed Critical Kyorin Pharmaceutical Co. Ltd

2017-05-16 Publication of BRPI0816814A2 publication Critical patent/BRPI0816814A2/pt

2021-08-31 Publication of BRPI0816814B1 publication Critical patent/BRPI0816814B1/pt

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 305
239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
125000001424 substituent group Chemical group 0.000 claims abstract description 39
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 34
201000010099 disease Diseases 0.000 claims abstract description 27
108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 claims abstract description 26
102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 claims abstract description 26
125000002947 alkylene group Chemical group 0.000 claims abstract description 16
230000001404 mediated effect Effects 0.000 claims abstract description 16
238000002360 preparation method Methods 0.000 claims description 133
-1 5-tetrazolyl Chemical group 0.000 claims description 112
229910052739 hydrogen Inorganic materials 0.000 claims description 64
239000001257 hydrogen Substances 0.000 claims description 63
125000001072 heteroaryl group Chemical group 0.000 claims description 33
150000002431 hydrogen Chemical group 0.000 claims description 29
125000000753 cycloalkyl group Chemical group 0.000 claims description 26
125000000623 heterocyclic group Chemical group 0.000 claims description 25
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
239000003937 drug carrier Substances 0.000 claims description 18
229910052757 nitrogen Inorganic materials 0.000 claims description 18
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
229910052760 oxygen Inorganic materials 0.000 claims description 15
229920006395 saturated elastomer Polymers 0.000 claims description 15
125000005843 halogen group Chemical group 0.000 claims description 14
125000005842 heteroatom Chemical group 0.000 claims description 13
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
239000001301 oxygen Chemical group 0.000 claims description 12
150000003839 salts Chemical class 0.000 claims description 12
229910052717 sulfur Chemical group 0.000 claims description 12
239000011593 sulfur Chemical group 0.000 claims description 12
239000003814 drug Substances 0.000 claims description 11
229910052799 carbon Inorganic materials 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
208000035475 disorder Diseases 0.000 claims description 7
206010012289 Dementia Diseases 0.000 claims description 6
206010012601 diabetes mellitus Diseases 0.000 claims description 6
208000027089 Parkinsonian disease Diseases 0.000 claims description 5
206010034010 Parkinsonism Diseases 0.000 claims description 5
125000004093 cyano group Chemical group *C#N 0.000 claims description 5
125000002993 cycloalkylene group Chemical group 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
238000007920 subcutaneous administration Methods 0.000 claims description 4
208000020925 Bipolar disease Diseases 0.000 claims description 3
201000011240 Frontotemporal dementia Diseases 0.000 claims description 3
208000024827 Alzheimer disease Diseases 0.000 claims description 2
206010009900 Colitis ulcerative Diseases 0.000 claims description 2
208000011990 Corticobasal Degeneration Diseases 0.000 claims description 2
208000011231 Crohn disease Diseases 0.000 claims description 2
208000023105 Huntington disease Diseases 0.000 claims description 2
208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
208000001132 Osteoporosis Diseases 0.000 claims description 2
206010033128 Ovarian cancer Diseases 0.000 claims description 2
206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
208000018737 Parkinson disease Diseases 0.000 claims description 2
208000000609 Pick Disease of the Brain Diseases 0.000 claims description 2
206010040047 Sepsis Diseases 0.000 claims description 2
201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 2
206010014599 encephalitis Diseases 0.000 claims description 2
208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
201000006417 multiple sclerosis Diseases 0.000 claims description 2
201000002528 pancreatic cancer Diseases 0.000 claims description 2
208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
201000002212 progressive supranuclear palsy Diseases 0.000 claims description 2
206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 15
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 9
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 2
125000004043 oxo group Chemical group O=* 0.000 claims 2
125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 1
239000002131 composite material Substances 0.000 claims 1
101150090422 gsk-3 gene Proteins 0.000 claims 1
208000013223 septicemia Diseases 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 270
238000000034 method Methods 0.000 abstract description 117
125000000217 alkyl group Chemical group 0.000 abstract description 59
125000001188 haloalkyl group Chemical group 0.000 abstract description 15
239000003112 inhibitor Substances 0.000 abstract description 7
238000004519 manufacturing process Methods 0.000 abstract description 6
KWMUSDDZNYHIBR-UHFFFAOYSA-N 3-amino-1h-quinolin-2-one Chemical class C1=CC=C2NC(=O)C(N)=CC2=C1 KWMUSDDZNYHIBR-UHFFFAOYSA-N 0.000 abstract description 2
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 170
239000000243 solution Substances 0.000 description 160
239000002253 acid Substances 0.000 description 156
239000007787 solid Substances 0.000 description 153
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 144
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 126
238000005160 1H NMR spectroscopy Methods 0.000 description 124
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 124
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 122
BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 116
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 91
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 90
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 82
239000011541 reaction mixture Substances 0.000 description 80
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 75
239000002244 precipitate Substances 0.000 description 74
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 71
238000001914 filtration Methods 0.000 description 68
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 67
239000002904 solvent Substances 0.000 description 64
238000004949 mass spectrometry Methods 0.000 description 58
239000005457 ice water Substances 0.000 description 55
UWXIKAZQXAYFPT-UHFFFAOYSA-N 1,4-benzoxazepine Chemical compound O1C=CN=CC2=CC=CC=C12 UWXIKAZQXAYFPT-UHFFFAOYSA-N 0.000 description 49
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 45
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
125000003003 spiro group Chemical group 0.000 description 45
238000006243 chemical reaction Methods 0.000 description 44
235000019439 ethyl acetate Nutrition 0.000 description 42
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
239000012043 crude product Substances 0.000 description 39
PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical compound C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-UHFFFAOYSA-N 0.000 description 37
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
125000003118 aryl group Chemical group 0.000 description 33
239000000725 suspension Substances 0.000 description 32
239000000460 chlorine Substances 0.000 description 31
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 30
238000009472 formulation Methods 0.000 description 30
ZCXLTWVZYXBHJS-UHFFFAOYSA-N 1,2-benzoxazepine Chemical compound O1N=CC=CC2=CC=CC=C12 ZCXLTWVZYXBHJS-UHFFFAOYSA-N 0.000 description 29
230000008569 process Effects 0.000 description 29
238000003786 synthesis reaction Methods 0.000 description 27
230000015572 biosynthetic process Effects 0.000 description 26
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
125000003710 aryl alkyl group Chemical group 0.000 description 25
235000019441 ethanol Nutrition 0.000 description 25
239000000706 filtrate Substances 0.000 description 25
238000003756 stirring Methods 0.000 description 25
238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 24
239000004480 active ingredient Substances 0.000 description 23
238000003818 flash chromatography Methods 0.000 description 23
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
238000004440 column chromatography Methods 0.000 description 21
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 19
239000002585 base Substances 0.000 description 19
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 19
238000012360 testing method Methods 0.000 description 19
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
239000012267 brine Substances 0.000 description 18
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 18
239000003921 oil Substances 0.000 description 18
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
235000019198 oils Nutrition 0.000 description 17
235000002639 sodium chloride Nutrition 0.000 description 17
229910052938 sodium sulfate Inorganic materials 0.000 description 17
235000011152 sodium sulphate Nutrition 0.000 description 17
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
239000007832 Na2SO4 Substances 0.000 description 16
229920001577 copolymer Polymers 0.000 description 16
239000002552 dosage form Substances 0.000 description 16
125000004475 heteroaralkyl group Chemical group 0.000 description 16
239000007788 liquid Substances 0.000 description 16
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
239000008103 glucose Substances 0.000 description 15
229910000104 sodium hydride Inorganic materials 0.000 description 15
239000003826 tablet Substances 0.000 description 15
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
102000001267 GSK3 Human genes 0.000 description 14
108060006662 GSK3 Proteins 0.000 description 14
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
125000003545 alkoxy group Chemical group 0.000 description 14
230000000694 effects Effects 0.000 description 14
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
229910000041 hydrogen chloride Inorganic materials 0.000 description 14
NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 14
238000010992 reflux Methods 0.000 description 14
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
239000002775 capsule Substances 0.000 description 13
239000000839 emulsion Substances 0.000 description 13
239000000843 powder Substances 0.000 description 13
238000013270 controlled release Methods 0.000 description 12
238000001816 cooling Methods 0.000 description 12
238000001704 evaporation Methods 0.000 description 12
230000008020 evaporation Effects 0.000 description 12
TYHXIJJQIJKFSO-UHFFFAOYSA-N n'-pyridin-2-ylethane-1,2-diamine Chemical compound NCCNC1=CC=CC=N1 TYHXIJJQIJKFSO-UHFFFAOYSA-N 0.000 description 12
239000000126 substance Substances 0.000 description 12
GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 12
239000003795 chemical substances by application Substances 0.000 description 11
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 11
239000000796 flavoring agent Substances 0.000 description 11
239000002953 phosphate buffered saline Substances 0.000 description 11
229910000027 potassium carbonate Inorganic materials 0.000 description 11
125000006308 propyl amino group Chemical group 0.000 description 11
208000024891 symptom Diseases 0.000 description 11
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 10
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
239000003054 catalyst Substances 0.000 description 10
210000004027 cell Anatomy 0.000 description 10
239000002502 liposome Substances 0.000 description 10
GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 9
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 9
239000005977 Ethylene Substances 0.000 description 9
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 9
229930006000 Sucrose Natural products 0.000 description 9
125000000304 alkynyl group Chemical group 0.000 description 9
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
238000002451 electron ionisation mass spectrometry Methods 0.000 description 9
150000002148 esters Chemical class 0.000 description 9
239000000284 extract Substances 0.000 description 9
239000007924 injection Substances 0.000 description 9
238000002347 injection Methods 0.000 description 9
238000000746 purification Methods 0.000 description 9
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
239000005720 sucrose Substances 0.000 description 9
239000003981 vehicle Substances 0.000 description 9
NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 8
125000003342 alkenyl group Chemical group 0.000 description 8
125000004453 alkoxycarbonyl group Chemical group 0.000 description 8
239000012230 colorless oil Substances 0.000 description 8
229940079593 drug Drugs 0.000 description 8
239000008187 granular material Substances 0.000 description 8
239000000463 material Substances 0.000 description 8
229920002527 Glycogen Polymers 0.000 description 7
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
241001465754 Metazoa Species 0.000 description 7
125000004391 aryl sulfonyl group Chemical group 0.000 description 7
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 7
125000004122 cyclic group Chemical group 0.000 description 7
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 7
235000013355 food flavoring agent Nutrition 0.000 description 7
235000003599 food sweetener Nutrition 0.000 description 7
235000011187 glycerol Nutrition 0.000 description 7
229940096919 glycogen Drugs 0.000 description 7
239000008176 lyophilized powder Substances 0.000 description 7
229910052943 magnesium sulfate Inorganic materials 0.000 description 7
235000019341 magnesium sulphate Nutrition 0.000 description 7
239000012044 organic layer Substances 0.000 description 7
239000000546 pharmaceutical excipient Substances 0.000 description 7
239000011734 sodium Substances 0.000 description 7
235000017557 sodium bicarbonate Nutrition 0.000 description 7
229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
239000003765 sweetening agent Substances 0.000 description 7
239000006188 syrup Substances 0.000 description 7
235000020357 syrup Nutrition 0.000 description 7
230000000699 topical effect Effects 0.000 description 7
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 6
125000004390 alkyl sulfonyl group Chemical group 0.000 description 6
239000012300 argon atmosphere Substances 0.000 description 6
125000005161 aryl oxy carbonyl group Chemical group 0.000 description 6
244000309464 bull Species 0.000 description 6
125000004432 carbon atom Chemical group C* 0.000 description 6
IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
238000000576 coating method Methods 0.000 description 6
239000003086 colorant Substances 0.000 description 6
238000007796 conventional method Methods 0.000 description 6
ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 6
238000004821 distillation Methods 0.000 description 6
239000008101 lactose Substances 0.000 description 6
125000004433 nitrogen atom Chemical group N* 0.000 description 6
238000007911 parenteral administration Methods 0.000 description 6
229920000573 polyethylene Polymers 0.000 description 6
235000011181 potassium carbonates Nutrition 0.000 description 6
239000000047 product Substances 0.000 description 6
QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
239000006144 Dulbecco’s modiﬁed Eagle's medium Substances 0.000 description 5
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
229910010084 LiAlH4 Inorganic materials 0.000 description 5
108091000080 Phosphotransferase Proteins 0.000 description 5
239000004698 Polyethylene Substances 0.000 description 5
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Classifications

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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/20—Spiro-condensed systems

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PCT/US2008/010700 WO2009035684A1 (fr)	2007-09-12	2008-09-12	Aminoquinolones spirocycliques utilisées en tant qu'inhibiteurs de gsk-3

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CN (2)	CN102344457B (fr)
BR (1)	BRPI0816814B1 (fr)
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CN102421784B (zh)	2009-03-11	2015-09-30	杏林制药株式会社	作为gsk-3抑制剂的7-环烷基氨基喹诺酮

2008
- 2008-09-12 EP EP08830522.2A patent/EP2203459B1/fr active Active
- 2008-09-12 CA CA2699152A patent/CA2699152C/fr not_active Expired - Fee Related
- 2008-09-12 MX MX2010002662A patent/MX2010002662A/es active IP Right Grant
- 2008-09-12 JP JP2010524878A patent/JP5373799B2/ja not_active Expired - Fee Related
- 2008-09-12 WO PCT/US2008/010700 patent/WO2009035684A1/fr not_active Ceased
- 2008-09-12 BR BRPI0816814-8A patent/BRPI0816814B1/pt not_active IP Right Cessation
- 2008-09-12 CN CN201110206924.3A patent/CN102344457B/zh not_active Expired - Fee Related
- 2008-09-12 KR KR1020107007774A patent/KR101597841B1/ko not_active Expired - Fee Related
- 2008-09-12 CN CN200880115090A patent/CN101855229A/zh active Pending
- 2008-09-12 US US12/678,120 patent/US8476261B2/en not_active Expired - Fee Related
2013
- 2013-05-24 US US13/902,589 patent/US8901112B2/en active Active

Also Published As

Publication number	Publication date
AU2008299862A1 (en)	2009-03-19
US20110034436A1 (en)	2011-02-10
HK1163060A1 (en)	2012-09-07
EP2203459B1 (fr)	2016-03-16
CA2699152C (fr)	2015-11-24
JP2010539170A (ja)	2010-12-16
KR20100067668A (ko)	2010-06-21
WO2009035684A1 (fr)	2009-03-19
US20140005184A1 (en)	2014-01-02
CN102344457A (zh)	2012-02-08
CA2699152A1 (fr)	2009-03-19
CN102344457B (zh)	2015-07-22
AU2008299862A8 (en)	2010-04-22
BRPI0816814A2 (pt)	2017-05-16
JP5373799B2 (ja)	2013-12-18
US8476261B2 (en)	2013-07-02
MX2010002662A (es)	2010-04-09
CN101855229A (zh)	2010-10-06
KR101597841B1 (ko)	2016-02-26
EP2203459A1 (fr)	2010-07-07
US8901112B2 (en)	2014-12-02

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BRPI0816814B1 (pt)	2021-08-31	Composto, composição farmacêutica e uso de um composto
CA2755120C (fr)	2017-05-16	7-cycloalkylaminoquinolones comme inhibiteurs de la gsk-3
US9481666B2 (en)	2016-11-01	Substituted dihydroisoquinolinone compounds
CA3149926A1 (fr)	2021-03-11	Composes inhibiteurs de rip1 et leurs procedes de fabrication et d'utilisation
MD3788045T2 (ro)	2023-09-30	Compuși inhibitori ai RIP1 și procedee de obţinere și utilizare a acestora
CN109476635B (zh)	2021-07-13	用于治疗疾病的二取代吡唑类化合物
BR112014022106B1 (pt)	2022-08-02	Derivados macrocíclicos, combinação, composição e usos na fabricação de um medicamento para o tratamento de doenças
TW201827437A (zh)	2018-08-01	作為hiv整合酶抑制劑之四環雜環化合物
CN106458987B (zh)	2019-09-24	用于治疗疾病诸如糖尿病的吡咯烷gpr40调节剂
US20130012496A1 (en)	2013-01-10	Benzazepine compound
CN119894908A (zh)	2025-04-25	Egfr抑制剂和其用途
AU2008299862B2 (en)	2013-08-08	Spirocyclic aminoquinolones as GSK-3 inhibitors
HK1163060B (en)	2016-05-27	Spirocyclic aminoquinolones as gsk-3 inhibitors
US20260048131A1 (en)	2026-02-19	Bifunctional compounds and uses thereof
US20250382292A1 (en)	2025-12-18	Compounds for treating light chain amyloidosis
HK40061625A (en)	2022-06-02	Pyridine oxynitride, preparation method therefor and use thereof
HK1165425B (en)	2016-07-15	7-cycloalkylaminoquinolones as gsk-3 inhibitors

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